Most neurodegenerative disorders are associated with aggregates of ubiquitinated proteins, such as Lewy bodies in Parkinson's disease and neurofibrillary tangles in Alzheimer's disease. Although the etiology of the sporadic forms of these disorders remains elusive, these observations support our central hypothesis: proteasome impairment is an important risk factor in neurodegeneration. Proteasome dysfunction is thus expected to be a pivotal link between environmental and genetic factors that are implicated in triggering neurodegeneration. Based on our previous studies we propose to develop and characterize a novel Drosophila model of neurodegeneration to address the mechanisms that underlie neuronal loss associated with proteasome impairment. The main objective of this proposal is to determine the relationship among impairment of proteasome function, accumulation and aggregation of ubiquitinated proteins in intracellular inclusions and neuronal cell death in an in vivo Drosophila model of neurodegeneration. Three specific aims are proposed: 1.Genetically over express the proteasome which will allow us to investigate if this has an impact on aging and neurodegeneration. 2. Manipulate levels of ATP and AIRAP protein to investigate how this will affect proteasome activity. 3. Investigate the role of proteasome activity on axonal transport. Our studies with this innovative Drosophila model of neurodegeneration will clarify the relationship among proteasome impairment, ATP levels and neurodegeneration. They will also reveal potential therapeutic strategies to prevent the accumulation of ubiquitinated proteins associated with most neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: In a variety of neurological disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis, aggregates of ubiquitinated proteins are detected in neuronal inclusions in selective sets of neurons. The mechanisms leading to the formation of such abnormal aggregates and their role in the progression of neurodegeneration is unknown. We are interested to investigate the role of the proteasome, which is the most important cellular protein degradation system, as a factor in the pathogenesis of these neurodegenerative diseases.